Project Summary/Abstract Diabetes manifests when the body?s demand for insulin exceeds the capacity of pancreatic ? cells to produce and secrete it. This can arise due to autoimmune destruction of ? cells (Type I diabetes), a combination of insulin resistance and subsequent ? cell failure (Type II diabetes), or primary genetic defects that impair ? cell development and function including maturity onset diabetes of the young (MODY) and Wolfram Syndrome (WS). As of 2012, approximately 29.1 million Americans suffered from diabetes, resulting in direct medical costs of $176 billion (National Diabetes Statistics Report, 2014). In order to meet the needs of this growing patient population, top pharmaceutical companies such as Eli Lily, AstraZeneca, and Novo Nordisk have active diabetes pipelines to identify and test molecules that enhance ? cell function. Unfortunately, drug discovery efforts in this space are hampered by the absence of a ? cell drug screening platform that captures both patient genetics and the complex phenotypes of primary ? cells. To meet this need, Regenerative Medical Solutions (RMS) has pioneered a simple proprietary protocol to produce islet-like clusters (ILC) containing multiple pancreatic endocrine cell types, including insulin-producing ?-like cells, from human induced pluripotent stem cells (iPSC). RMS has demonstrated that these ILC, when derived from healthy donor iPSC, capture many of the complex phenotypes of primary ? cells, including expression of key marker genes and robust glucose stimulated insulin secretion. In order to demonstrate the utility of the platform for detection of pathologies associated with specific patient genotypes, RMS will generate ?-like cells from MODY patients with well-characterized mutations in the glucokinase (GCK) gene and patients with WS, caused by mutations in the wolframin gene (WSF1). The ability of ILC harboring these mutations to replicate the well-established deficits in ? cell function seen in the patients will be demonstrated, and initial quantities of the cells will be made available to RMS?s existing customers. In a follow-on Phase II proposal, ?-like cells from patients with more complex genetics (i.e. Type I and Type II diabetes) will be developed for use as high-throughput screening platforms for drug discovery.